Introduction

In normotensive, healthy subjects, ageing is associated with structural arterial changes, including arterial dilatation and loss of vascular compliance, that influence left ventricular (LV) load and induce geometric remodelling, leading to increased relative wall thickness without increase in overall LV mass.^1,2 In hypertensive patients, older age is associated with higher prevalence of LV hypertrophy, but it is uncertain whether this is due to age itself or to age-related increased prevalences of concomitant diseases, including coronary or valvular heart disease, diabetes mellitus, and renal impairment influencing LV structure and function.^3,4

Several treatment trials have demonstrated that reduction of blood pressure induces regression of elevated LV mass in hypertensive patients.^5,6,7 Theoretically, age-related changes in capacitance vessels and myocardium could attenuate regression of LV hypertrophy in older hypertensive patients. However, so far the influence of age on LV hypertrophy regression has not been addressed in a large-scale longitudinal study. Thus, the aim of the present study was to assess the impact of age on LV hypertrophy regression during antihypertensive treatment in the subset of hypertensive patients with electrocardiographic LV hypertrophy without known diabetes, or coronary or valvular heart disease who were recruited into the Losartan Intervention For Endpoint reduction in hypertension (LIFE) echocardiography substudy.⁷

Methods

Patient population

The LIFE echocardiography substudy was prospectively planned to enroll >10% of participants in the parent study for annual echocardiographic follow-up. The main LIFE study randomized 9194 patients aged 55–80-years with essential hypertension (baseline casual blood pressure 160–200/95–115 mmHg) and electrocardiographic LV hypertrophy (according to Cornell voltage-duration or Sokolow–Lyon voltage criteria) to 4.6-year, double-blind treatment with losartan- compared to atenolol-based therapy evaluating the effect of treatment on morbid events and regression of LV hypertrophy.⁷ From the main LIFE study population, 960 patients were recruited into the LIFE echocardiographic substudy, of whom 753 returned for the year 4 echocardiogram. Among these, 567 patients (75%) were free of concomitant diabetes mellitus, previous myocardial infarction, and >grade 1 aortic and mitral regurgitation, and thus were eligible for the present study (Table 1). Patients were classified as having isolated systolic hypertension if systolic blood pressure was 140 and diastolic blood pressure <90 mmHg, respectively, at clinic baseline visits.⁸ Pulse pressure was calculated as the difference between sitting clinic systolic and diastolic blood pressures, and the mean blood pressure as sitting diastolic blood pressure plus 1/3 pulse pressure. Urinary albumin excretion was assessed as urinary albumin/creatinine ratio measured in morning spot urine obtained at the clinic visits, and considered increased if the ratio exceeded 3.5 mg/mmol.⁹ All patients gave informed consent to participate in the LIFE echocardiographic substudy, which was approved by local and regional committees on ethics in all participating centres and countries.

Table 1 - Baseline characteristics of the 752 patients who had readable echocardiograms both at baseline and after 4 years in the LIFE echocardiography substudy when divided into patients with (n=185, excluded patients) or without (n=567, present study population) concurrent diabetes, or known coronary or valvular heart disease.

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Doppler echocardiography

Organization, patient recruitment, protocol, and echocardiographic methods used in the LIFE echocardiographic substudy have been previously published.^10,11 All studies were sent to the Cornell Echocardiography Reading Center for blinded interpretation by an experienced echocardiographer. Measurements were made according to the American Society of Echocardiography standards.^12,13 Relative wall thickness was calculated at end-diastole as posterior wall thickness/internal radius, endocardial fractional shortening as the ratio (diastolic–systolic LV internal diameter)/diastolic LV internal diameter, the LV ejection fraction by the Teichholz method, and LV mass using an autopsy-validated formula.^14,15,16,17 LV geometry was assessed from LV mass/body surface area and relative wall thickness in combination.¹⁸ Relative wall thickness >0.43 was considered increased.¹⁸ LV hypertrophy was considered present when LV mass/body surface area exceeded 116 g/m² in men, and 104 g/m² in women, respectively.¹⁹ Midwall shortening was calculated using a previously validated method.^20,21 Stroke volume was calculated by an invasively validated method.²² Pulse pressure/stroke volume ratio was calculated as an indirect measure of systemic arterial stiffness. The leading edge of transmitral Doppler flow pattern obtained at leaflet tips was traced to derive the ratio between peak early and atrial LV filling phase (E/A) and deceleration time. Atrial filling fraction was calculated as the ratio of the A-wave time velocity integral to the total diastolic time velocity integral. Isovolumic relaxation time was recorded using pulsed Doppler in the LV outflow tract identifying inflow and outflow profiles simultaneously. Aortic and mitral regurgitation were assessed by colour Doppler using previously described 4-point grading systems.^23,24 Supine blood pressure measured by arm cuff sphygmomanometer at the end of the echocardiogram was used in calculation of haemodynamic variables. Heart rate was measured from the echocardiographic recordings.

Statistics

Data management and analysis were performed using the SPSS 10.0 (SPSS, Chicago, IL, USA) software. Data are presented as means.d., or median and range for continuous variables, and as percentages for categorical variables. Between-group comparisons were made by ANOVA, ²-statistics, or unpaired Student's t-test, as appropriate. Owing to skewed distribution, urine albumin/creatinine ratio data were log transformed. Bivariate correlations were assessed by Pearson's correlation coefficients. Multiple linear regression analysis was used to identify covariates of year 4 reduction in LV mass. Two-tailed P<0.05 was considered statistically significant.

Results

The total study population (567 patients) was divided by median age (65 years) into middle-aged and older groups. The older group included more women and patients with isolated systolic hypertension or albuminuria at baseline and had persistently higher pulse pressure, urinary albumin/creatinine ratio, LV mass/body surface area, pulse pressure/stroke volume ratio, E/A ratio, and atrial filling fraction throughout the study (Tables 2 and 3). Over 4 years, blood pressure and LV mass/body surface area were significantly reduced in the total study population from 173/99 to 144/83 mmHg and 121 to 99 g/m², respectively (both P<0.001). The year 4 reduction in mean blood pressure, pulse pressure, LV mass/body surface area, and pulse pressure/stroke volume ratio did not differ between middle-aged and older patients. However, the older group had higher prevalence of residual LV hypertrophy after 4 years (31 vs 16%), with a preponderance of eccentric geometry (Table 4). The prevalence of LV hypertrophy showed parallel decreases from higher values at baseline in both older and middle-aged patients (75 and 59%, respectively). The difference in E/A ratio and atrial filling fraction between middle-aged and older patients remained significant also when correcting for the difference in LV mass and systolic blood pressure.

Table 2 - Baseline prevalences of women and isolated systolic hypertension and year 4 changes in blood pressure, heart rate, and urinary albumin/creatinine ratio in the middle-aged and older groups of patients.

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Table 3 - Echocardiographic findings in middle-aged and older patients at baseline and after 4 years.

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Table 4 - Left ventricular geometry at baseline and after 4 years in the middle-aged and older groups of patients (both P<0.001).

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In bivariate correlations, age was positively related to baseline systolic blood pressure (r=0.24), pulse pressure (r=0.38), LV mass (r=0.08), pulse pressure/stroke volume (r=0.27), and log urinary albumin creatinine ratio (r=0.16), and negatively related to diastolic blood pressure (r=-0.31) and body mass index (r=-0.17, all P<0.001). Age was also positively associated with 4 year change in pulse pressure (r=0.08) and log albumin/creatinine ratio (r=0.20, both P<0.05). However, when controlling for systolic blood pressure, the correlation between age and LV mass at baseline was no longer statistically significant.

Based on the results of univariate analyses, a multivariate analysis was created assessing the influence of age on 4 year reduction in LV mass. Controlling for baseline LV mass, gender, body mass index, study treatment, and 4 year reduction in pulse pressure and log albuminuria, age was not identified as an independent covariate of 4 year reduction in LV mass (multiple R²=0.40, P<0.01) (Table 5).

Table 5 - Influence of age on 4 year reduction in LV mass assessed in multivariate analysis (multiple R²=0.40, P<0.001).

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Discussion

The present study evaluates the impact of age on LV hypertrophy regression during long-term antihypertensive treatment in a large series of patients with essential hypertension and electrocardiographic LV hypertrophy without known concurrent disease, including diabetes, or coronary and valvular heart disease. The study shows that 4 year reduction in LV hypertrophy assessed by echocardiography does not differ between middle-aged and older patients when a similar reduction in blood pressure is induced. As older patients had a larger initial LV mass/body surface area, an even greater reduction could have been expected in this group. From this, a minor impact of age on LV hypertrophy regression could be suggested, although no independent correlation with 4 year change in LV mass was found in multivariate analysis.

The finding that older age was not independently associated with higher LV mass when systolic blood pressure was taken into account is in agreement with previous reports, suggesting that the effect of age on LV structure in hypertensive subjects is mostly mediated through a higher systolic blood pressure.^1,6,7,8,25 However, the present study population differed from those previously studied in having higher prevalences of isolated systolic hypertension, LV hypertrophy, and albuminuria.

LV geometry has been demonstrated to influence both LV function and prognosis.²⁶ Although older patients had more pronounced LV hypertrophy both at baseline and after 4 years of antihypertensive treatment, LV geometry changed significantly during the study period. The study demonstrates that concentric LV hypertrophy, the prognostically most unfavourable form of LV hypertrophy in hypertensive patients, is virtually eliminated after 4 years of antihypertensive treatment, in spite of a somewhat suboptimal systolic blood pressure control. Still, older patients had significantly more residual eccentric LV hypertrophy after 4 years, which may be explained by the persistently higher pulse pressure and presumed more subclinical coronary heart disease and longer duration of hypertension in the older group, all of which are associated with more pronounced LV hypertrophy, although the duration of hypertension was not systematically assessed in the present study.^27,28

In the present study, older age was also associated with persistently more impaired diastolic relaxation, demonstrated by longer isovolumic relaxation time, lower E/A ratio, and higher atrial filling fraction, as also previously reported by others.²⁹ Theoretically, these findings may be related to the higher LV mass in older patients. However, age-related differences in wall structure independent of wall thickness may also be operative. This hypothesis is supported by several findings, including the lack of a significant relation between LV mass and diastolic Doppler LV filling indices in this and other studies in older patients with hypertension,³⁰ our finding that E/A ratio and atrial filling fraction remained significantly different between older and middle-aged patients when corrected for the difference in LV mass and blood pressure, and, finally, by results from studies of cardiac ageing in spontaneously hypertensive rats demonstrating an increased fibrous tissue content in older compared to younger spontaneously hypertensive rats.³¹

In conclusion, in up-to-80-year-old patients with hypertension and electrocardiographic LV hypertrophy, age does not significantly attenuate LV hypertrophy regression assessed by echocardiography during 4 years of antihypertensive treatment. However, residual LV hypertrophy is more prevalent in older patients as a consequence of higher initial LV mass.

References

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Acknowledgements

We acknowledge Paulette A Lyle for assistance with the preparation of the manuscript.